👤 Josélia Alencar Lima

Elevated atherogenic lipoproteins increase risk of atherosclerotic cardiovascular disease (ASCVD), though long-term risk for adults without ASCVD who have low-normal levels has not been well described. This study used pooled data from 16,384 individuals in 3 population-based prospective cohorts. At baseline all participants were without ASCVD and were not taking lipid-lowering therapy. We evaluated ASCVD events by baseline LDL-C, non-HDL-C and apoB, including low-normal values. ASCVD risk was assessed using multivariable Cox proportional hazards. The study cohort had a mean age of 52 (SD 18) years with 56.5% women, 64.7% of White race and 35.3% of Black race. Over a median follow-up of 18.8 years, unadjusted ASCVD event incidence was similar for adults with baseline LDL-C < 70 mg/dL and 70 to 99 mg/dL, and higher with LDL-C ≥ 100 mg/dL; trends were similar for non-HDL-C and apoB categories. Compared to having baseline LDL-C 70 to 99 mg/dL, LDL-C < 70 mg/dL was associated with similar ASCVD risk (adjusted HR 1.16 [95% Confidence Interval, 95% CI 0.90-1.50]) and LDL-C ≥ 130 mg/dL was associated with higher risk (adjusted HR 1.31 [95% CI 1.14-1.50]) after multivariable adjustment; adults with non-HDL-C ≥ 160 mg/dL or apoB ≥ 90 mg/dL also had higher risk after multivariable adjustment. Among adults without ASCVD not taking lipid-lowering therapy at baseline, ASCVD risk for adults with low-normal and high-normal LDL-C, non-HDL-C and apoB was similar, and their risk remained less than in adults with elevated lipoproteins. These findings emphasize the importance of achieving normal atherogenic lipoprotein levels for primary prevention of ASCVD from early adulthood through middle age. Show less

Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary atherosclerosis. Functional aspects of high-density lipoprotein (HDL), including cholesterol transfer capacity, may contribute to cardiovascular risk heterogeneity in FH. To investigate whether cholesterol transfer to HDL and other HDL-related parameters are associated with coronary artery disease (CAD) in patients with heterozygous FH (HeFH). Fifty-three genetically confirmed FH patients (mean age: 49.2 years; 73.6% female) were included. Twenty-seven had plaques, while 26 had no vessel abnormalities as determined by coronary computed tomography angiography. The transfer of both unesterified and esterified cholesterol (UC and EC) to HDL, as well as HDL antioxidant capacity, particle size, and subfractions, plasma concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON-1) activity were assessed. Family history of premature CAD (P < .028) and tendinous xanthomas (P = .014) were more frequent in those with plaques. No differences were found in apolipoprotein (apo) B, LDL-C, LDL-C year score, lipoprotein(a), non-HDL-C, apo A-I, HDL-C, HDL subfractions, or triglycerides. Transfer of lipids to HDL and antioxidant capacity did not differ between the groups. LCAT concentrations and PON-1 activity were also similar. In contrast, CETP concentration was higher in those with plaques (P < .008). However, only family history of early CAD (odds ratio [OR]: 4.12, 95% CI, 1.23-13.80, P = .022) and xanthomas (OR: 3.65, 95% CI, 1.06-12.60, P = .040) were independently associated with plaques. Among patients with HeFH, no HDL-related parameter was independently associated with subclinical CAD. Show less

Lp(a) (lipoprotein[a]) is a known cardiovascular risk factor; however, its role in cardiac remodeling and functional changes over time across diverse racial and ethnic groups remains underexplored. MESA is a prospective multi-ethnic cohort study of individuals without a history of cardiovascular disease on enrollment (2000-2002), conducted across 6 sites in the United States. Participants with baseline Lp(a) measurements and cardiac magnetic resonance imaging at both baseline and 10-year follow-up exam were included. Lp(a) was treated as both a log-transformed continuous variable (per SD log) and a categorical variable based on data-driven Lp(a) terciles. Multivariable regression models adjusted for sociodemographic, and cardiovascular risk factors, including coronary artery calcium and interim myocardial infarction, were used to assess associations between Lp(a) and longitudinal changes in left ventricular and atrial structure and function over a decade across different racial/ethnic groups. A total of 2366 participants were included. The average age at baseline was 60±9 with 53% women, 43% White, 24% Black, 21% Hispanic, and 12% Chinese. Each 1-SD increase in log-transformed Lp(a) was associated with an increase in left ventricular end-systolic volume index (β, 0.60 [95% CI, 0.02-1.18]), and left atrial minimum volume index (β, 0.81 [95% CI, 0.09-1.52]), and a decline in left ventricular ejection fraction (β, -0.75 [95% CI, -1.34 to -0.17]), and total left atrial emptying fraction (β, -1.17 [95% CI, -2.09 to -0.24]) in Hispanic subjects over a decade. No significant associations were seen in White, Black, or Chinese participants. The observed findings persisted after adjusting for coronary artery calcium, interim myocardial infarction, and atrioventricular decoupling, and when Lp(a) was treated as a categorical variable with race-specific terciles. Elevated Lp(a) levels were independently associated with maladaptive left ventricular and left atrial remodeling in Hispanic adults over a decade, while no statistically significant relationships were observed in White, Black, and Chinese participants. This suggests a unique susceptibility of Hispanic individuals to Lp(a)-mediated cardiovascular remodeling, independent of ischemic pathways. Show less

Spinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited ataxias worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation and functional capacity maximization. Symptomatic treatment guidelines are scarce, leaving decisions to physicians' discretion. The lack of studies on SCA3 symptom management hinders therapy standardization. The aim of this study was to investigate medication-usage patterns among SCA3 mutation carriers and controls included in the multicentric European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) cohort. We conducted a retrospective cross-sectional analysis of the medication taken by ESMI participants enrolled in the study between 2016 and 2023. Medication being used at the most recent follow-up visit available was categorized according to the Anatomical Therapeutic Chemical system. Comparisons between groups were performed using nonparametric tests for continuous variables and Fisher's exact test for categorical variables. In addition, a retrospective longitudinal analysis was conducted to study the impact of medication subclasses on disease progression, using linear mixed-effects models adjusted for relevant covariates. A total of 474 participants were included, comprising 344 SCA3 mutation carriers and 130 controls. Compared with controls, SCA3 subjects took more vitamins, mineral supplements, muscle relaxants, and medications targeting the nervous system. Psychoanaleptics and vitamins were introduced early in the disease course, whereas most other subclasses were initiated in mid-to-late stages, coinciding with the onset of neurological symptoms. Substantial disparities in medication usage were observed across the study centers. None of the medication subclasses commonly used by patients with SCA3 showed a significant impact on disease progression. This is the first study to explore medication usage patterns in SCA3 mutation carriers. Our study provides a comprehensive overview of the medications administered in SCA3 and underscores the importance of collaborative efforts toward achieving standardized clinical practices in the management of this disease. Show less

The present study investigated the effect of perinatal programming combined with exposure to a western diet on gene expression related to inflammation, neurodegeneration, and synaptic plasticity in the hippocampus of adult rats. Male rats from mothers fed either a standard diet or a western diet during gestation and lactation were used. All pups received only the standard chow diet from the 25th postnatal day (PND), and their body weight was analysed. Rats from the two groups fed the maternal diet were then divided on the 195 Adult rats submitted to a western diet during pregnancy and lactation showed signs of metabolic programming. In addition, glucose and total protein were found to have increased in the serum. The effect of acute exposure to a western diet is increased cholesterol. The western diet decreased gene expression of inflammatory factors ( Acute exposure to a western diet in adulthood alters pre-translational pathways ( Show less

The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear. In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1. A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group. The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.). Show less

Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safety of treatment with pemigatinib, an oral, potent, selective FGFR1-3 inhibitor, in patients with advanced FGFR-altered CNS tumors. FIGHT-207 was a single-arm, open-label, phase 2 study of pemigatinib in patients with advanced solid tumors harboring FGFR fusions/rearrangements or other mutations. Patients received pemigatinib 13.5 mg once daily until disease progression or unacceptable toxicity. Endpoints included tumor response and safety. Of the 13 patients with CNS tumors in FIGHT-207, 10 had glioblastoma. Fibroblast growth factor receptor alterations were FGFR3-TACC3 fusions (n = 9), FGFR1 K656E mutations (n = 2), FGFR1 N546K mutation (n = 1), and FGFR1-MITF fusion (n = 1). Three patients (23%) displayed objective responses (1 complete, 2 partial). Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors. Show less

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial tumors. Evidence suggests that these types of tumors may have high recurrence rates. In this context, the purinergic system, oxidative stress, and inflammation are important signaling pathways involved in the cancer's pathophysiology. This study aimed to evaluate the sociodemographic and diagnostic profiles, as well as assess the purinergic signaling, immunological, and redox profiles, of patients after PitNET resection. We collected sociodemographic data and the patients' diagnostic profiles. We also collected blood samples to analyze glycemia, triglycerides, albumin, and ATP levels. The ectonucleotidase activity was determined in peripheral blood mononuclear cells (PBMCs). In addition, we evaluated their redox and immunological profiles. There was a prevalence of gonadotropic macroadenoma derived from PIT-1 cells. We found that patients included in the PitNET group had increased glycemia, serum ATP levels, and ATP hydrolysis in PBMCs. Analyzing their immunological profiles, we found that patients had increased levels of IL-6, IL-10, and TNF, while the IL-27 level was decreased. Regarding their redox profiles, PitNET patients had increased levels of ROS and protein carbonylation. Unexpectedly, patients also showed increased levels of non-protein thiols (NPSHs), total thiols (PSHs), and ascorbic acid. Thus, the dysregulation of purinergic signaling sustained chronic inflammation and oxidative imbalance in PitNET patients for a long time after surgical resection. These data suggest that patients with PitNETs require long-term accompanying to prevent cancer recurrence prognosis. The biomarkers highlighted in this study may be good tools to help the medical approaches. Show less

The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control. Show less

Atherosclerotic vascular changes can begin during childhood, providing risk for cardiovascular disease (CVD) in adulthood. Identifiable risk factors such as dyslipidemia accelerate this process for some children. The apolipoprotein B (APOB) gene could help explain the inter-individual variability in lipid levels among young individuals and identify groups that require greater attention to prevent CVD. A cross-sectional study was conducted with school-aged children and adolescents in Ouro Preto, Minas Gerais. The study evaluated cardiovascular risk factors' variables and XbaI polymorphism in the APOB gene for associations with increased total cholesterol (TC). The prevalence of increased TC was notably high, reaching 68.9% in the study population. Carriers of the variant T allele were 1.45 times more likely to develop increased TC in a dominant model (1.09-1.94, p = 0.011). After adjustments, excess weight and a family history of dyslipidemia interacted significantly with XbaI polymorphism in increased TC, resulting in Odds Ratio of 1.74 (1.11-2.71, p = 0.015) and 2.04 (1.14-3.67, p = 0.016), respectively. The results suggest that XbaI polymorphism in the APOB gene may affect the lipid profile of Brazilian children and adolescents and could contribute to the CVD in adulthood. Show less

Interleukin 27 (IL-27) is a cytokine that regulates susceptibility to Leishmania infantum infection in humans and experimental models. This cytokine has not yet been described in canine leishmaniasis (CanL). Therefore, we investigated whether IL-27 has a regulatory role in CanL. The EBI3 and p28 subunits of IL-27 were measured in splenic leukocytes culture supernatant from dogs with CanL and compared to control dogs. We also correlated EBI3 and p28 levels with IL-21, anti-L. infantum antibodies and parasite loads. We performed functional assays followed by IL-27 blockade and measured parasite loads, production of cytokines in splenic leukocytes culture supernatant, and the expression of PD-1, CTLA-4, phospho-Stat-1/3, T-bet, GATA3 and nitric oxide production (NO). Both IL-27 subunits increased in the supernatant of dogs with CanL compared to control dogs. EBI3 and p28 levels showed a moderate positive correlation with IL-21 (r = 0.67, p < 0.0001 and r = 0.45, p < 0.012, respectively), and the EBI3 subunit was positively associated with anti-L. infantum IgG antibodies (r = 0.38, p < 0.040) and parasite load (r = 0.47, p < 0.009). IL-27 and IL-21 participate of immune responses in CanL. IL-27 may be associated with the failure of immunity to control parasite replication via upregulation of the expression of PD-1, CTLA-4, T-bet and NO in splenic leukocytes from dogs with CanL. These findings suggest that the pathways regulated by IL-27 are involved in CanL pathogenesis in the host, and may be targets for new therapies. Show less

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early-phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies. Show less

Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients. Show less

Tuberculosis (TB) is the leading cause of pleural exudative effusions. Inflammatory markers, such as IFNγ and ADA, have been used as proxies for its diagnosis. We evaluated ex vivo levels of several cytokines in 83 pleural effusion specimens from patients with TB (including 10 with HIV co-infection) and 26 patients with other pleuritis using multiplex and ELISA assays. IL-6 and IL-27 levels were higher (p ≤ 0.04) in TB patients, regardless of the HIV status and the approach. IL-2, IL-4, IL-8, IFNγ, TNF and G-CSF showed variable results depending on the assay. This warranty these markers to be further validated. Show less

The present study describes the expression of genes in the Longissimus dorsi muscle related to meat quality of hair lambs finished in an Integration Crop-Livestock system. Twenty-eight non-castrated lambs of two breeds, Somalis Brasileira and Santa Inês, at 120 ± 15 days of age, with an average initial live weight of 18 ± 3.1 kg, were kept in a pasture-based finishing system with supplementation. Upon reaching 28 kg body weight, animals were sent for slaughter. Samples of the Longissimus dorsi and Biceps femoris muscle were harvested for analyses of gene expression and physicochemical properties. Significant differences were detected between the breeds for tissue and chemical composition, whereas the physical aspects did not differ. We observed the expression of six genes related to lipid synthesis (acetyl-CoA carboxylase [ACACA], fatty acid synthase [FAS], stearoyl-CoA desaturase [SCD], lipoprotein lipase [LPL], cell death-inducing DFFA-like effector A [CIDEA], and thyroid hormone responsive [THRSP]) and six genes related to molecular synthesis (myostatin [MSTN], growth differentiation factor 8 [GDF8], insulin-like growth factor 1 [IGF1], insulin-like growth factor 2 [IGF2], delta-like 1 homolog [DLK1], and growth hormone receptor [GHr]) in both breeds. The Santa Inês breed and the Somalis Brasileira showed similar expression patterns of genes related to lipogenesis and myogenesis of the Longissimus dorsi muscle, with the exception of the THRSP gene, in which the Somalis Brasileira have more receptors for the action of thyroid hormones, which resulted in greater thickness of fat in the carcass (subcutaneous fat) and higher lipid content in the chemical composition of the meat. Show less

The clinically important anticoagulant heparin, a member of the glycosaminoglycan family of carbohydrates that is extracted predominantly from porcine and bovine tissue sources, has previously been shown to inhibit the β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key drug target in Alzheimer's Disease. In addition, heparin has been shown to exert favourable bioactivities through a number of pathophysiological pathways involved in the disease processes of Alzheimer's Disease including inflammation, oxidative stress, tau phosphorylation and amyloid peptide generation. Despite the multi-target potential of heparin as a therapeutic option for Alzheimer's disease, the repurposing of this medically important biomolecule has to-date been precluded by its high anticoagulant potential. An alternative source to mammalian-derived glycosaminoglycans are those extracted from marine environments and these have been shown to display an expanded repertoire of sequence-space and heterogeneity compared to their mammalian counterparts. Furthermore, many marine-derived glycosaminoglycans appear to retain favourable bioactivities, whilst lacking the high anticoagulant potential of their mammalian counterparts. Here we describe a sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus that displays high inhibitory potential against BACE-1 (IC Show less

Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aβ plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of β-amyloid protein (Aβ protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3β enzymes involved in AD. Show less

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases. Show less

To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR - ) GIPR. Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR -  tumors. Twenty-eight out of 56 (50%) GIPR -  tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR -  tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors. Show less

Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA). To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR. MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes ( A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants. Show less

The aim of this review was to assess whether the presence of rs9939609 and rs17782313 polymorphisms increase the risk for obesity among children and adolescents. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and it was registered in PROSPERO. The search was performed in the PubMed/Medline, The Cochrane Library, and Web of Science databases. The risk of bias of the studies was accessed using the Newcastle-Ottawa scale and JBI Critical Appraisal Checklist for Analytical. The search of the databases retrieved 859 references. Twelve studies were eligible to be included in this systematic review. Five studies founded a positive association between overweight and obesity in children and adolescents with the presence of the rs17783213 and four studies with rs9939609. Three studies did not find an association between overweight and obesity in children and adolescents with the presence of rs17782313 or rs9939609. One found a protective effect for obesity in individuals with risk A allele referring to rs9939609, one found a synergistic effect in relation to the presence of polymorphisms rs17782313 and rs9939609 for obese phenotype, and one observed that the presence together of the rs9939609, rs17782313, and rs12970134 MC4R were significant for the presence of obesity in children and adolescents. The results suggest that depending on the population evaluated and ethnicity, the polymorphisms rs17782313 and rs9939609 could be associated with overweight and obesity in children and adolescents. Show less

To investigate whether an exercise intervention using the VIVIFRAIL© protocol has benefits for inflammatory and functional parameters in different frailty status. This is a randomized clinical trial in an outpatient geriatrics clinic including older adults ≥60 years. For each frailty state (frail, pre-frail and robust), forty-four volunteers will be randomly allocated to the control group (n = 22) and the intervention group (n = 22) for 12 weeks. In the control group, participants will have meetings of health education while those in the intervention group will be part of a multicomponent exercise program (VIVIFRAIL©) performed five times a week (two times supervised and 3 times of home-based exercises). The primary outcome is a change in the inflammatory profile (a reduction in inflammatory interleukins [IL-6, TNF- α, IL1beta, IL-17, IL-22, CXCL-8, and IL-27] or an increase in anti-inflammatory mediators [IL-10, IL1RA, IL-4]). Secondary outcomes are change in physical performance using the Short Physical Performance Battery, handgrip strength, fatigue, gait speed, dual-task gait speed, depressive symptoms, FRAIL-BR and SARC-F scores, and quality of life at the 12-week period of intervention and after 3 months of follow-up. We expect a reduction in inflammatory interleukins or an increase in anti-inflammatory mediators in those who performed the VIVIFRAIL© protocol. The results of the study will imply in a better knowledge about the effect of a low-cost intervention that could be easily replicated in outpatient care for the prevention and treatment of frailty, especially regarding the inflammatory and anti-inflammatory pathways involved in its pathophysiology. Brazilian Registry of Clinical Trials (RBR-9n5jbw; 01/24/2020). Registred January 2020. http://www.ensaiosclinicos.gov.br/rg/RBR-9n5jbw/ . Show less

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features. Show less

The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy. Show less

Androgen deprivation therapy (ADT) is widely used in the treatment of testosterone-dependent prostate carcinomas. ADT often increases plasma LDL and HDL cholesterol and triglycerides. The aim was to test whether ADT changes the transfer of lipids to HDL, an important aspect of this metabolism and HDL protective functions, and related parameters. Sixteen volunteers with advanced prostate carcinoma submitted to pharmacological ADT or orchiectomy had plasma collected shortly before and after 6 months of ADT. In vitro transfer of lipids to HDL was performed by incubating plasma with donor emulsion containing radioactive lipids by 1 h at 37 °C. After chemical precipitation of apolipoprotein B-containing lipoprotein, the radioactivity of HDL fraction was counted. ADT reduced testosterone to nearly undetectable levels and markedly diminished PSA. ADT increased the body weight but glycemia, triglycerides, LDL and HDL cholesterol, HDL lipid composition and CETP concentration were unchanged. However, ADT increased the plasma unesterified cholesterol concentration (48 ± 12 vs 56 ± 12 mg/dL, p = 0.019) and LCAT concentration (7.15 ± 1.81 vs 8.01 ± 1.55μg/mL, p = 0.020). Transfer of unesterified (7.32 ± 1.09 vs 8.18 ± 1.52%, p < 0.05) and esterified cholesterol (6.15 ± 0.69 vs 6.94 ± 1.29%, p < 0.01) and of triglycerides (6.37 ± 0.43 vs 7.18 ± 0.91%, p < 0.001) to HDL were increased after ADT. Phospholipid transfer was unchanged. Increase in transfer of unesterified and esterified cholesterol protects against cardiovascular disease, as shown previously, and increased LCAT favors cholesterol esterification and facilitates the reverse cholesterol transport. Thus, our results suggest that ADT may offer anti-atherosclerosis protection by improving HDL functional properties. This could counteract, at least partially, the eventual worse effects on plasma lipids. Show less

The central melanocortin system is composed of neurons that express either the proopiomelanocortin (POMC) or the agouti-related protein (AgRP). POMC is cleaved in bioactive peptides, including the α-melanocyte-stimulating hormone (α-MSH). α-MSH activates the melanocortin-4 receptor (MC4R) inducing satiety, whereas AgRP acts as an inverse agonist of MC4R. However, only limited information is available regarding possible area-specific differences in the interaction between α-MSH and AgRP terminals on MC4R-expressing cells. Therefore, the objective of the present study was to compare the distribution pattern of α-MSH and AgRP terminals on the perikarya of MC4R-expressing neurons. We performed a triple-label immunofluorescence reaction in brain series of MC4R-reporter mice to visualize MC4R-expressing neurons together with AgRP and α-MSH terminals. POMC and AgRP neurons project to areas that contain MC4R-expressing cells, although several brain nuclei exhibit AgRP and α-MSH terminals, but they do no express MC4R, while other brain areas contain MC4R-expressing cells and receive no apparent innervation of AgRP and POMC neurons. AgRP terminals make more presumptive appositions than α-MSH on the soma of MC4R-expressing neurons of the medial preoptic area and paraventricular nucleus of the hypothalamus (Pa). Additionally, a higher percentage of MC4R cells receive at least one presumptive apposition from AgRP terminals in the median preoptic nucleus and Pa, compared to α-MSH appositions. Thus, our study revealed area-specific differences in the interaction between α-MSH and AgRP terminals and the soma of MC4R-expressing neurons. These findings provide new insights about the relationship between first- and second-order neurons of the central melanocortin system. Show less

Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process. Plasma and tumor levels of ANGPTL-4 were higher in CC in comparison to other groups. A positive association was verified between plasmatic ANGPTL-4 and NFκB levels in tumor from CC. In WSC, we identified an association between the plasmatic ANGPTL-4, IL-15, and IL-10 in tumor and IL-15 in MES. Increased levels of NFκB and TNF-R1 in MES were detected in CC in comparison to WSC. Specifically in CC-group, a positive correlation was found between ANGPTL-4 levels and those of IL-1β, TNF-α, and NFκB in tumor, along with an association between ANGPTL-4 levels with IL-1β and MCP-1 levels in tumor; and ANGPTL-4 and IL-1β levels in MES. We studied 102 patients, who were divided into three groups: control patients (C, n=37), cancer patients with a stable weight (WSC, n=23), and cancer-cachexia patients (CC, n=42). Samples of plasma, tumor, mesenteric (MES) and subcutaneous adipose tissue were removed for the determination of ANGPTL-4 levels and other proinflammatory factors. ANGPTL-4 levels were higher in plasma and tumor of CC-group, and positively associated with pro-inflammatory and pro-tumorigenic factors. Our results suggest an opposite effect of ANGPTL-4 depending on the concentration and presence of cachexia. Show less

An exploratory analysis using proteomic strategies in blood serum of patients with bipolar disorder (BD), and with other psychiatric conditions such as Schizophrenia (SCZ), can provide a better understanding of this disorder, as well as their discrimination based on their proteomic profile. The proteomic profile of blood serum samples obtained from patients with BD using lithium or other drugs (N=14), healthy controls, including non-family (HCNF; N=3) and family (HCF; N=9), patients with schizophrenia (SCZ; N=23), and patients using lithium for other psychiatric conditions (OD; N=4) were compared. Four methods for simplifying the serum samples proteome were evaluated for both removing the most abundant proteins and for enriching those of lower-abundance: protein depletion with acetonitrile (ACN), dithiothreitol (DTT), sequential depletion using DTT and ACN, and protein equalization using commercial ProteoMiner® kit (PM). For proteomic evaluation, 2-D DIGE and nanoLC-MS/MS analysis were employed. PM method was the best strategy for removing proteins of high abundance. Through 2-D DIGE gel image comparison, 37 protein spots were found differentially abundant (p<0.05, Student's t-test), which exhibited ≥2.0-fold change of the average value of normalized spot intensities in the serum of SCZ, BD and OD patients compared to subject controls (HCF and HCNF). From these spots detected, 13 different proteins were identified: ApoA1, ApoE, ApoC3, ApoA4, Samp, SerpinA1, TTR, IgK, Alb, VTN, TR, C4A and C4B. Proteomic analysis allowed the discrimination of patients with BD from patients with other mental disorders, such as SCZ. The findings in this exploratory study may also contribute for better understanding the pathophysiology of these disorders and finding potential serum biomarkers for these conditions. Show less